Comments

Comments on Primary Papers and News

This is an interesting paper and follows the initial findings of Wang et al., 2000 (same first author), where it was shown that Aβ42 has a very high-affinity interaction with the α7 nicotinic acetylcholine receptor. The intracerebrovascular infusion of Aβ42 into mice that induced certain tau-phospho-epitopes and was blocked by the small molecule PTI-125 is intriguing. This compound works at the nanomolar range, which is very potent, by preventing binding of the scaffolding protein, filamin A (FLNA), to the nicotinic receptor.

The authors claim in Table 1 that they have been able to stimulate the FLNA/receptor interaction with several α7-specific ligands (methyllycaconitine, aBgTx, PNU282987). However, all three of these agents are potent α7 binders (24 nM for PNU and single-digit nanomolar for the other two). It would have been good if they had used lower doses (say, 10-fold over Ki but not 250- to 1,000-fold over Ki) for these compounds. The α7 agents that have been used clinically and have shown promise typically act in the concentrations that are closer to the Ki; that is, functional assays typically overestimate the concentrations needed to predict animal and/or human efficacy. This is important because one wants to know whether the agonists act as functional antagonists if used at these higher doses in a chronic manner, or whether it is true functional agonism. If the α7 agonists work only at these higher concentrations, the implications for their clinical use are not immediately apparent. Of course, that is different if one focuses on compounds with similar mechanisms of actions as PTI-125.

Furthermore, the method of co-immunoprecipitation is at best semi-quantitative, but the authors based their quantitative pharmacological interpretation on these assays. The authors show also a functional impairment of α7 signaling through either Aβ infusion or from AD brains, which can be ameliorated by PTI-125. While they state in the discussion that PTI-125 is orally bioavailable in rats, they used it intraperitoneally. It would be nice to get concentration ranges for the PTI-125-treated animals to see how it relates to the in-vitro or ex-vivo experiments.

Clearly, the authors went to great lengths to extend their earlier findings that the α7 receptor is a main conduit of Aβ42-mediated toxicity. It is a very dense paper, and it may explain Aβ42 toxicity and how that could be blocked or ameliorated by PTI-125. It will be interesting to see parts of these findings extended into in-vivo efficacy studies.